SUMMARY: Linezolid is a new antibiotic with activity against Mycobacterium tuberculosis in vitro and
in vivo. This study aims to evaluate the efficacy and safety of linezolid in the treatment of extensively
drug-resistant tuberculosis (XDR-TB). We used a linezolid-containing regimen in the treatment of 14
XDR-TB patients. Two years of individualized chemotherapy regimens were adopted on the basis of the
patients' medication history and the results of drug susceptibility testing. The patients received 600 mg
of linezolid twice a day for the first 1–2 months, followed by once a day thereafter. Eleven patients
(78.6z) showed significant improvement in clinical symptoms. Chest computed tomography revealed
that 10 patients (71.4z) showed cavity closure. Smear conversion and culture conversion were achieved
in all 14 patients (100z) with an average of 64 and 63 days, respectively. The exact proportions of serious and minor adverse events determined by linezolid were 21.4z (3/14) and 64.3z (9/14), respectively. These data show that linezolid-containing chemotherapy for the treatment of XDR-TB may significantly improve clinical symptoms, promote lesion absorption and cavity closure, and accelerate sputum conversion. Further, adverse reactions can be tolerated and resolved with suitable intervention.
In recent years, extensively drug-resistant tuberculosis
(XDR-TB) (i.e., bacillary resistance to rifampicin,
isoniazid, fluoroquinolone, at least one second-line injectable drug [e.g., amikacin, kanamycin, or capreomycin]) has been identified in more than 59 countries. Because of changes in international travel and migration
patterns, the threat of XDR-TB is global (1–3). Treatment outcomes for XDR-TB are poor because of the
lack of effective drugs (4). Linezolid (LZD) was the first
oxazolidinone to be developed and introduced for clinical use, and it exhibited good activity against different
species of mycobacteria, including resistant mycobacterial strains (5). The minimal inhibitory concentration
to inhibit 90z growth (MIC90) of Mycobacterium
tuberculosis was in the range of 1–2 mg/L for LZD. The
MICs of LZD against nontuberculous mycobacteria are
higher than the MICs of LZD against M. tuberculosis
(6–8). Recent reports of case series have suggested that
LZD may be effective in treating multidrug-resistant
(MDR)-TB and XDR-TB. Long-term LZD application,
however, has been associated with myelosuppression
and neurotoxicity (9,10). To further evaluate the clinical
efficacy and safety of LZD in the treatment of XDRTB, we took the lead in adopting LZD-containing
chemotherapy to treat 14 XDR-TB patients in China
and have reported a case series with no comparison
group.

Fourteen patients who were diagnosed with XDR-TB
using microbiological tests between April 2009 and
January 2010 were enrolled. The inclusion criteria were
as follows: (i) age, 18–66 years; (ii) M. tuberculosis in
the sputum culture that was confirmed using the
BACTEC MIGT 960 Mycobacterial Testing System
(Becton Dickinson, Sparks, Md., USA) within 60 days
before the regimen was initiated and diagnosed as XDR
according to the World Health Organization (WHO)
criteria (11); (iii) active TB suggested by chest
radiography; and (iv) informed consent obtained from
the patients. The exclusion criteria were as follows: (i)
allergic to LZD; (ii) severe cardiovascular, liver, kidney,
or blood system diseases or other serious illnesses; (iii)
mental illness; and (iv) pregnancy or lactation. On the
basis of these criteria, we enrolled 10 men and 4 women
who were 31–66 years of age (average age, 45 ± 10
years). The study protocol was approved by the Ethics
Committee of the Shanghai Pulmonary Hospital.
In our study, 2 years of individualized treatment regimens were adopted according to each patient's drug-use
history and the results of recent drug susceptibility testing, and the treatment was started as soon as informed
consent was obtained. The laboratory is quality controlled within the WHO proficiency system. Drugs were
selected according to the 5 groups of anti-TB drugs
recommended by WHO in 2008 (11). All the patients
received 600 mg of LZD (Zyvox}; Pfizer Inc., New
York, N.Y., USA) twice a day at the beginning of the
regimen for a maximum period of 2 months, followed
by once a day thereafter. The complete XDR-TB treatment regimen listed in Table 1 was started at the same
time as the initiation of the LZD regimen.
Hypoxemia was defined as a partial pressure of

Duration of 600 mg LZD twice a day (days)
Duration of LZD administration (months)
Time to symptom improvement (days)
Time to cavity shrink (months)
Time to cavity closure (months)1)
Time to smear conversion (days)
Time to culture conversion (days)

42
6
8
1
4
42
8

7
6
7
2
—
8
8

30
11
7
2
5
63
8

35
6
7
1
6
35
63

14
8.5
2
1
—
87
91

42
7
14
1
2
70
77

14
6
2
1
5
210
210

29
2
2
2
4
70
77

56
6
7
2
3
70
84

21
6
5
5
6
180
150

21
6
7
2
3
14
28

14
6
14
2
3
21
28

42
2
7
2
—
14
28

21
6
14
3
—
21
28

1):

—, not closed.

oxygen (PaO2) value in the range of 60–80 mmHg using
arterial blood gas analysis. Respiratory failure was defined as PaO2 lower than 60 mmHg using arterial blood
gas analysis. Neutropenia was defined as a leukocyte
count lower than 4.0 × 109/L. Moderate anemia was
defined as hemoglobin level in the range of 6–9 g/dL.
Severe anemia was defined as hemoglobin level lower
than 6 g/dL.
All the 14 patients with XDR-TB exhibited pulmonary TB (Table 1); the longest disease duration was 20
years and the shortest was 2 years, with an average of
8.8 ± 6.0 years. All the patients were HIV-negative.
Three patients had diabetes mellitus; 4, tracheal and
bronchial TB; and 2, tuberculous pleurisy, 1 of whom
had an additional complication of right tuberculous
pyopneumothorax. Three patients had hypoxemia and 4
had respiratory failure; these patients were supplied
with O2 tubes. Two patients had chronic obstructive
pulmonary disease and 2 had hypoproteinemia. All the
14 patients complained of cough and sputum expectoration. Five patients complained of chest tightness and
shortness of breath, 3 had hemoptysis, and 4 had fever
with body temperature higher than 38.59C; 3 of these 4
patients had temperatures higher than 39.59C.
In the 14 XDR-TB cases, the longest duration of LZD
treatment was 11 months and the shortest duration was

2 months, with an average of about 6.5 months (Table
2). The body temperature of 3 of the 4 patients with
fever returned to normal on the 2nd day after treatment,
and the body temperature of the remaining patient
returned to normal on the 5th day. Cough and sputum
expectoration of all the 14 patients were significantly
improved. Chest tightness, short of breath, diabetes
mellitus, and hemoptysis were also improved; all 4
patients with respiratory failure recovered after 1 week,
while 2 of the 3 patients with hypoxemia recovered and
the remaining patient improved. The 2 patients with
hypoproteinemia improved after chemotherapy and
supportive therapy. Altogether, 11 patients (78.6z)
showed significant improvement in clinical symptoms.
The weight of 13 patients was maintained or increased.
Six months after LZD-containing treatment, chest computed tomography revealed that 10 patients (71.4z)
showed cavity closure. Smear conversion was achieved
in all 14 patients (100z). The onset of smear conversion
occurred after 8 to 210 days of therapy, with an average
of 64 days. Culture conversion was achieved in all 14
patients (100z). The time from the start of LZD-containing treatment to culture conversion ranged from 8 to
210 days, with an average of 63 days. However, neither
smear nor culture conversion times were related to the
duration of 1,200 mg LZD treatment (r ＝ －0.151 and
510

Table 3. Adverse event of linezolid in the treatment of XDR-TB

r ＝ －0.138, respectively; P ＝ 0.605 and P ＝ 0.637,
respectively) (Table 2).
The results of the blood test, urine test, blood coagulation index, and liver and kidney function tests and the
electrocardiogram (ECG) of each patient were monitored every week. None of the 14 patients had liver or
renal damage. The ECG showed no prominent abnormalities. One patient had diabetic nephropathy with
positive result for urine protein; this returned to normal
after symptomatic treatment. Three patients intermittently tested positive for urine protein, but their renal
function (serum creatinine and urea nitrogen) was normal. Four patients (28.6z) had gastrointestinal adverse
reactions such as nausea after about 2–4 weeks of treatment with 600 mg of LZD twice a day, but these
resolved spontaneously after the dose of LZD was
reduced to 600 mg once a day. Six patients (42.9z) developed hematological adverse reactions, including 1
case of neutropenia, 4 cases of asymptomatic moderate
anemia, and 1 case of severe anemia, in the 2nd week of
treatment with 600 mg LZD twice a day. The bone marrow function of the patient with severe anemia normalized 2 weeks after blood transfusion and the discontinuation of LZD. Anemia did not recur when treatment
was resumed with 600 mg LZD once a day. Mild to
moderate peripheral neuropathy affecting the lower
limbs was observed in 3 patients (21.4z) between the
2nd and 3rd months. The clinical manifestations were
numbness, pain, and tingling in the toes. One patient
complained of difficulty in walking. These symptoms
resolved after concomitant treatment with vitamin B6
and methylcobalamin. Two patients developed optic
neuropathy in the 6th month, which completely resolved
in both patients 1 month after the discontinuation of
LZD. The exact proportions of serious and minor adverse events determined by LZD were 21.4z (3/14) and
64.3z (9/14), respectively (Table 3).
XDR-TB is the most serious form of drug-resistant
TB. Its clinical treatment outcome is extremely poor
with high and rapid mortality attributable to the lack of
effective treatments. China is one of the world's 27
countries with the highest burden of MDR-TB/XDRTB (12,13). We took the lead in using a LZD-containing
regimen in China to treat 14 patients with XDR-TB.
Our results show that at least in the short term, using a
LZD-containing regimen to treat XDR-TB can significantly improve clinical symptoms, promote lesion
absorption and cavity closure, and accelerate sputum
negative conversion.
There is no unanimous opinion on the dose and duration of LZD treatment (14–16). Although no statistically significant difference was observed in the efficacy of
LZD at the doses of 600 mg and 1,200 mg per in our
small-sample study, it is still not clear whether a longer
duration of LZD treatment at the dose of 1,200 mg per
day might be more effective for treating XDR-TB
patients. The suitable dose of LZD for treating XDRTB patients needs to be further demonstrated in clinical
practice. According to the literature and our experience,
we recommend that patients initially receive 1,200 mg of
LZD twice a day and that the dosage be reduced to 600
mg once a day or once every 2 days after 4–8 weeks. The
total course of treatment can be up to 6–12 months.
The incidence of adverse reactions attributable to

long-term application of LZD is high (9,10,17). Our
results show that adverse events attributable to LZD
treatment included gastrointestinal and hematological
reactions as well as optic and peripheral neuropathy.
These adverse events were resolved upon discontinuation of or reduction in the dosage of LZD. Among the
14 patients treated with LZD-containing regimens for
an average of 6 months, 3 patients discontinued or temporarily discontinued the treatment because of an adverse reaction; others discontinued the treatment because of financial reasons. We believe that despite the
high incidence of adverse reactions, some of them serious, the overall drug program would not be affected as
long as close observation and timely and correct intervention are performed. Hematological adverse reactions
occurred in the 2nd month after treatment initiation.
Therefore, it is necessary to monitor blood and other indices weekly at the beginning. The onset of peripheral
neuritis was observed after 2–3 months of therapy; the
onset was earlier than that observed in some reports
(10,14). Visual loss occurred later, usually around the
6th month of treatment. Both clinicians and patients
should be alert.
Our results indicate that treating XDR-TB with a
LZD-containing regimen may have high efficacy and
may improve the quality of life. Meanwhile, patients
and clinicians should be fully aware of and monitor adverse reactions, and appropriate interventions should be
administered. In conclusion, we suggest that LZD be
recommended for the treatment of XDR-TB.
Acknowledgments We acknowledge the outstanding contributions from the technicians and nursing staff at Shanghai Pulmonary
Hospital. We also express our thanks to Fang Yuanyuan and Lv Yan
for their time and effort in data collection and patients follow-up.
This study was supported by the Key Project of Chinese National
Programs (grant no. 2009ZX10003–017).